Parathyroid hormone (PTH) is a secreted, 84 amino acid product of the mammalian parathyroid gland that controls serum calcium levels through its action on various tissues, including bone. Studies in humans with certain forms of PTH have demonstrated an anabolic effect on bone, and have prompted significant interest in its use for the treatment of osteoporosis and related bone disorders.
Using the N-terminal 34 amino acids of the bovine and human hormone for example, which by all published accounts are deemed biologically equivalent to the full length hormone, it has been demonstrated in humans that parathyroid hormone enhances bone growth particularly when administered in pulsatile fashion by the sub-cutaneous and intravenous routes. A slightly different form of PTH, human PTH(1-38) has shown similar results. Because of its only recent availability, the recombinant form of the full length, human hormone, i.e., human PTH(1-84) has not yet been studied in humans although studies in rats indicate an equipotent and in some respects somewhat improved efficacy in bone growth.
PTH preparations used in these studies have been reconstituted from fresh or lyophilized hormone, and incorporate various forms of carrier, excipient and vehicle. Most are prepared in water-based vehicles such as saline, or water acidified typically with acetic acid to solubilize the hormone. The majority of reported formulations also incorporate albumin as a carrier (see for example Reeve et al, Br. Med. J., 1980, 280:6228; Reeve et al, Lancet, 1976, 1:1035; Reeve et al, Calcif Tissue Res, 1976, 21:469; Hodsman et al, Bone Miner; 1990, 9(2):137; Tsai et al, J. Clin. Endocrinol Metab, 1989, 69(5):1024; Isaac et al, Horm Metab Res, 1980, 12(9):487; Law et al, J Clin Invest, 1983, 72(3): 1106; and Hulter, J. Clin evpertens, 1986, 2(4):360). Other reported formulations have incorporated an excipient such as mannitol, which is present either with the lyophilized hormone or in the reconstitution vehicle. Formulations representative of those employed for human studies include a human PTH(1-34) preparation consisting, upon reconstitution, of mannitol, heat inactivated human serum albumin, and caproic acid (a protease inhibitor) as absorption enhancer (see Reeve et al, 1976, Calcif. Tissue Res., 21, Suppl., 469-477); a human PTH(1-38) preparation reconstituted into a saline vehicle (see Hodsman et al, 1991, 14(1), 67-83); and a bovine PTH(1-34) preparation in aqueous vehicle pH adjusted with acetic acid and containing albumin. There is also an International Reference preparation which for human PTH consists of 100 ng of hormone ampouled with 250 .mu.g human serum albumin and 1.25 mg lactose (1981), and for bovine PTH consists of 10 .mu.g lyophilized hormone in 0.01M acetic acid and 0.1% w/v mannitol (see Martindale, The Extra Pharmacoepia, The Pharmaceutical Press, London, 29th Edition, 1989 at p. 1338).
Commercial exploitation of parathyroid hormone requires the development of a formulation that is acceptable in terms of storage stability and ease of preparation and reconstitution. Because it is a protein and thus far more labile than the traditionally small molecular weight drugs, however, the formulating of parathyroid hormone presents challenges not commonly encountered by the pharmaceutical industry. Furthermore, and unlike other proteins that have been formulated successfully, PTH is particularly sensitive to oxidation, and further requires that its N-terminal sequence remain intact in order to preserve bioactivity.
It is an object of the present invention to provide a pharmaceutically useful PTH preparation, particularly one comprising, as active ingredient, the full length form of human PTH.